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The first long-acting injectable drug regimen for HIV antiretroviral therapy (ART) has received regulatory approval in the United States (USA) and Canada [1,2]. A monthly intervaginal ring for HIV prevention has gained the recommendation of the WHO and a positive opinion from the European Medicines Agency (EMA) [3,4]. Recent efficacy findings for long-acting injectable HIV preexposure prophylaxis (PrEP) in the HIV Prevention Trials Network (HPTN) 083 and 084 trials hold enormous potential to reshape the HIV prevention landscape [5,6]. These important advances reflect a broad set of long-acting and extended delivery (LAED) regimens in the development for HIV treatment and prevention [7,8]. Additional LAED products in the HIV research pipeline include monthly oral regimens, extended-release implants, parenterally administered antibodies and multidose vaccine regimens. Although LAED regimens address a fundamental behavioural challenge by reducing the burden of daily pill adherence, retention in care remains critical for achieving clinical outcomes. Many existing barriers to equitable healthcare access, engagement and implementation will persist. Behavioural and social science can optimize the development, use and impact of LAED regimens. We see three key gaps that behavioural and social science research (BSSR) can address to strengthen future use of LAED regimens for HIV treatment and prevention: expand scientific understanding of end-user needs, desires and contexts to improve LAED product development; develop tools and approaches to support LAED regimen choice, use and care retention; and advance innovative healthcare delivery models to maximize equitable and efficient access to LAED HIV prevention and treatment regimens for improved impact (Table 1). These directions emerged from our independent assessment of presentations and discussions at a US National Institutes of Health (NIH) workshop examining behavioural aspects of LAED regimens for HIV prevention and treatment, which was attended by over 100 subject matter experts providing diverse expertise across clinical, behavioural, social and implementation sciences and community engagement [9]. Table 1 - Behavioural and Social Science Research priorities on long-acting and extended delivery regimens for HIV treatment and prevention. BSSR priority Overarching goal Related BSSR topics/methods Further scientific understanding of end-user needs, desires, and contexts through BSSR to improve LAED product development and testing. Advance novel LAED regimens that are desirable to end-users to optimize their future use. Qualitative methods (interviews, focus groups, ethnographic research)Discrete choice surveys with intended end-usersMixed-methods research with clinical trial participantsPlacebo trials or prototyping studiesCommunity engagement research Develop tools and approaches to support LAED regimen choice, use and care retention through BSSR. Support the safe and effective use of proven LAED regimens. Create decision tools to support person-centred, shared decision-making regarding LAED product initiation and discontinuationSupport oral medication adherence during any induction or discontinuation taper period required for LAED regimensAdvance care retention interventions to facilitate continuous/sustained use of LAED regimensUnderstand and address intersectional stigma as a fundamental barrier to care engagement and retention Advance innovative healthcare delivery models through BSSR to maximize equitable and efficient access to LAED regimens Maximize the reach and impact of LAED regimens for HIV treatment and prevention. Understanding provider and care factorsAdvance provider and workforce trainingInform development of innovative healthcare delivery models, including injection clinics, pharmacy-based care, community-based care and telemedicineGeolocation and time-motion analyses on care deliveryIntegrated care approachesDifferentiated care approachesAttending to cost and cost-effectiveness Expand scientific understanding of end-user needs, desires, and contexts to improve long-acting and extended delivery product development and testing BSSR improves understanding of end-user needs, desires and context-specific challenges and should be undertaken prior to development of novel LAED products and strategies, as well as during early and late-stage clinical trials. Early and iterative incorporation of user perspectives ensures that new LAED regimens are ‘gain creators’ or ‘pain relievers’ for both end-users/consumers and their providers. Human-centred design and consumer research approaches seek to understand the needs and desires of people for whom products will be designed [10,11]. Populations studied should reflect the sex, age and other diversity of the populations who will use the products. Qualitative BSSR methods including interviews, focus groups and ethnography are useful for understanding the interests of intended end-users. Focus groups with USA MSM revealed preferences for long-acting PrEP formulations that simplified their lives, and this view generated interest in biodegradable PrEP implants that do not require surgical removal [12]. Other important elicitation approaches include discrete choice experiments that ask respondents to rate contrasting options for hypothetical products, or ‘placebo trials’ that test use of inert product facsimiles [13–15]. BSSR also informs thoughtful design and conduct of LAED clinical trials [16–18]. Mixed methods BSSR (quantitative surveys and qualitative research) and community-based participatory research provide approaches for engaging community input to optimize clinical trial questions, design, recruitment and participation [19]. Systematic stakeholder consultation and development of culture and context-specific multimedia tools to support community engagement in clinical trials represent best practices. BSSR can help refine products that have advanced into clinical trials. Mixed methods BSSR research can identify reasons for differential product use across different clinical trial participants [20]. BSSR conducted with individuals not enrolled or poorly retained in LAED clinical trials provides understanding of individual and contextual factors that impact their product-related views or experience. HIV prevention and treatment product developers must ask, ‘How might we further improve this product and/or its delivery for you?’, at every stage of development and testing. Develop tools and approaches to support long-acting and extended delivery regimen choice, use and care retention Findings from BSSR have been important for optimizing the use and impact of novel healthcare regimens. For example, the benefits of highly efficacious oral HIV ART and PrEP prevention regimens have been constrained by suboptimal patient engagement and retention in care [21,22], requiring the development of associated BSSR-based interventions to improve care retention [23,24]. BSSR has been critical for understanding and addressing challenges to uptake and completion of HPV vaccine regimens, as well [25]. HIV-related LAED regimens that enter the marketplace will similarly require BSSR for best use. Decision tools are needed to clarify patient preferences around available regimens and to maximize patient satisfaction with regimen choice [26]. Decision tools have been helpful in the contraceptive field [27] and will facilitate LAED regimen selection and adoption for HIV treatment and prevention without coercion. Robust tools informed by decision science will attend to both deliberative reasoning and intuitive and emotional processes that guide decisions [28,29]. Decision tools could inform choices about LAED regimen discontinuation as well as initiation, as product preferences may shift over time. Oral regimens may precede and follow LAED regimens, and BSSR-informed strategies are needed to support their use. Current LAED regimens for HIV treatment or prevention require an oral induction phase to assure well tolerated use [30], although research is evaluating direct-to-inject approaches [31]. Oral medication is also needed to cover subtherapeutic (or sub-preventive) drug levels following discontinuation of certain long-acting regimens [32]. The interplay of oral and LAED regimens will require continued behavioural support for medication adherence. Retention in care has been pivotal for daily oral HIV prevention and treatment regimens and will be even more important for LAED regimens that have fixed dosing schedules. Missed or delayed clinical visits and product administration could lead to subtherapeutic drug levels and the potential for HIV acquisition or development of HIV drug resistance. Proven approaches that could assist retention and adherence to LAED regimens include case management, outreach and interactive digital support [23,33]. Efforts to reduce intersectional stigma surrounding HIV and key populations and to engage community-based product champions may facilitate sustained retention in prevention and treatment services [34–36]. Advance innovative healthcare delivery models to maximize equitable and efficient access to long-acting and extended delivery regimens Optimizing use of LAED regimens will require BSSR-informed health system innovations to proactively address constraints on LAED regimen delivery in health systems. BSSR methods can adapt healthcare delivery of LAED regimens in a manner that meets clients ‘where they are’, recognize that providers and payors constitute crucial gatekeepers, and promote equitable access to these innovations in HIV healthcare. The geographic and demographic distribution of new HIV infections reveals a disconnect between those who may benefit from oral PrEP and those who are prescribed it [37–39]. To avoid replicating these implementation inequities in the delivery of LAED regimens, BSSR-informed training of healthcare workers is needed to reduce implicit biases, practice skills and optimize coordinated care teams to avoid provider factors that have impeded consumer access to long-acting regimens in the fields of addiction and psychiatry [40,41]. New modes of service delivery are needed to reduce retention barriers and deliver LAED regimens equitably and efficiently. Community-based administration of LAED regimens through pharmacies or mobile vans combined with telemedicine and remote digital support could improve healthcare access [42,43]. Novel delivery strategies will benefit from BSSR-based stakeholder research, intervention development, time-motion analyses and geolocation studies. Further, integrative health systems will be important, as clients needing HIV treatment and prevention often have other chronic conditions and social service needs, including mental health and substance use disorders. BSSR can inform differentiated service delivery that tailors the type and intensity of services needed for LAED regimen success. Community-based health services may benefit some users, whereas individuals facing many challenges may need more frequent clinical contact and psychosocial support. Clinics that provide ‘on demand’ and integrative care have been able to effectively retain populations with extensive adherence barriers [44,45]. These approaches could be expanded as LAED regimens are used to engage more people in HIV prevention and treatment. BSSR can help ensure equitable access to LAED regimens through community engagement and health communications research, and by investigating how to address cost and other important structural barriers before these regimens are licensed. There is a need to engage policy makers and payors in evaluating data on LAED regimen cost-effectiveness. Modelling studies will require precise BSSR data to estimate the costs and benefits of these new regimens in different populations. BSSR will be instrumental in informing healthcare policies that make LAED regimens accessible to populations who will benefit from them. Conclusions A robust BSSR agenda should accompany all phases of LAED regimen development, clinical trials and implementation for HIV treatment and prevention. BSSR limitations include the potential for research samples and participation to diverge from real-world product users and use. BSSR still provides important opportunities to bridge implementation challenges so LAED regimens can be delivered in an equitable manner and achieve individual and public health goals. NIH is committed to advancing research on next-generation LAED regimens, and greatly encourages researchers to employ BSSR in the development, testing and implementation of these regimens to strengthen their ultimate use and impact. Acknowledgements The authors acknowledge Rivet Amico PhD, University of Michigan, USA, and Catherine Orrell, MBChB MMed MSc PhD, Desmond Tutu HIV Center, South Africa, as workshop co-Chairs and for their reading and suggestions on an early paper outline, along with Kenneth Mayer, MD, Fenway Institute, USA. The authors thank the workshop presenters and participants, as well as Pierre Paisible, Marlene Goldman, Marilyn Daly, Ian Anglin and all NIH staff who assisted with workshop logistics and note-keeping. T.M. wrote the first article draft and assisted with editing; W.C., E.S., T.S., N.C. and P.O.R. contributed writing and editing; M.J.S. prepared the original paper outline and contributed to writing and editing. The authors are members of the NIAID-NIMH Behavioral and Social Sciences Project Team (BSSPT), which planned the NIH workshop from which this manuscript was developed (’Looking to the Future: Behavioral Aspects of Long-Acting and Extended Delivery HIV Prevention and Treatment Regimens,’ May 13–14, 2019). The workshop was co-sponsored by the National Institute of Allergy and Infectious Disease (NIAID), the National Institute of Mental Health (NIMH), the NIH Office of Behavioral and Social Science Research (OBSSR), the NIH Office of Disease Prevention (ODP) and the NIH Office of AIDS Research (OAR). A weblink to information about the meeting is included in the reference section. The findings in this report are those of the authors and do not necessarily represent the views of the U.S. National Institutes of Health (NIH), the National Institute of Allergy and Infectious Disease (NIAID), the National Institute of Mental Health (NIMH) or other component NIH Institutes, Offices and Centers. Conflicts of interest There are no conflicts of interest.